Correspondence

Case 11-2008: Mental-Status Changes after Liver Transplantation

N Engl J Med 2008; 359:207-209July 10, 2008

Article

To the Editor:

We would like to make two points about the case of disseminated cryptococcosis in a liver-transplant recipient, discussed in the Case Records by Fishman et al. (April 10 issue).1 The first point concerns delayed diagnosis of this infection in patients with negative tests for human immunodeficiency virus infection. We believe that in the case presented, a correct diagnosis could have been suspected from day 13 onward on the basis of the patient's recurrent headaches. In immunocompromised patients, severe and persistent headache should prompt the performance of lumbar puncture.2

The second point is the low awareness among physicians of the diagnostic utility of cryptococcal antigen determination in serum.3 As shown in Table 1Table 1Diagnostic Value of Various Tests for Cryptococcal Meningitis in Recipients of Solid-Organ Transplants., of 153 organ-transplant recipients with cryptococcal meningitis in two reports, only 43 (28%) underwent serum cryptococcal antigen testing.4,5 This is surprising, since in transplant recipients and patients with AIDS, determination of serum cryptococcal antigen is highly sensitive and only slightly less specific than cryptococcal antigen determination in the cerebrospinal fluid. We thus advocate assessment of serum cryptococcal antigen in all immunocompromised patients with fever or headache lasting more than 3 days, whether or not meningeal signs are present.

Spinello Antinori, M.D.
Mario Corbellino, M.D.
University of Milan, 20122 Milan, Italy
spinello.antinori@unimi.it

5 References

1
Case Records of the Massachussets General Hospital (Case 11-2008). N Engl J Med 2008;358:1604-1613
Full Text | Web of Science | Medline

2
Antinori S. Signs of meningeal irritation: what is their diagnostic accuracy? Clin Infect Dis 2003;36:125-126
CrossRef | Web of Science | Medline

3
Antinori S, Radice A, Galimberti L, Magni C, Fasan M, Parravicini C. The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis. J Clin Microbiol 2005;43:5828-5829
CrossRef | Web of Science | Medline

4
Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome. Emerg Infect Dis 2001;7:375-381
CrossRef | Web of Science | Medline

5
Wu G, Vilchez RA, Eidelman B, Fung J, Kormos R, Kusne S. Cryptococcal meningitis: an analysis among 5,521 consecutive organ transplant recipients. Transpl Infect Dis 2002;4:183-188
CrossRef | Medline

To the Editor:

The case presentation notes that serologic testing showed the presence of antibodies against hepatitis B core and surface antigens; the test for hepatitis B surface antigen was negative. These results argue against the patient's having chronic hepatitis B disease. Fishman, in his discussion, states that the patient had end-stage liver disease due to hepatitis C and hepatitis B infections and alcoholism. With the positive tests for hepatitis B antibodies and the negative test for surface antigen, it is not likely that hepatitis B contributed to the patient's liver disease. Fishman also states that reactivation of hepatitis B might occur in the course of treatment after transplantation. Although this is not impossible, the likelihood that hepatitis B would become reactivated seems remote, even in an immunosuppressed person, with the serologic findings noted in the patient under discussion. Furthermore, it also seems very unlikely that the patient would have been at risk for invasive fungal disease as a result of his prior hepatitis B infection.

Mark Joy, M.D., J.D.
Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209
mark.joy@va.gov

Author/Editor Response

Clinical suspicion is the key element in establishing a diagnosis of cryptococcal meningitis or for any infection of the central nervous system in immunocompromised hosts. All such patients with suspected central nervous system infection or persistent headache should undergo imaging of the central nervous system and, if appropriate, lumbar puncture with suitable diagnostic evaluations.1 As Antinori and Corbellino note, the serum or cerebrospinal fluid cryptococcal antigen assay is a useful assay for the diagnosis of infection in both immunocompromised hosts with AIDS and immunocompromised hosts without AIDS. If the suspicion of cryptococcal infection is high, a positive assay should suggest that the choice for initial therapy is an amphotericin product and that echinocandin therapy is likely to be ineffective. In addition, early attention to the possibility of increased intracranial pressures and combination therapy (with flucytosine) should be considered. In contrast, cryptococcal antigen is less useful in management. As in this patient, persistent elevation of cryptococcal antigen may occur even in patients without demonstrably viable organisms. The development of highly sensitive, specific, and quantitative diagnostic tools for fungal infections would improve the management of such life-threatening episodes.

In immunocompromised patients with fungal infections, various factors that may have contributed to the risk for infection need to be considered and, if possible, ameliorated. These factors include recent intensification of immunosuppression, concomitant viral infections, and unusual epidemiologic exposures. Thus, active infections (e.g., with cytomegalovirus) are treated to enhance the response to antifungal therapy. The ability to reduce the intensity of immunosuppression must be considered on an individual basis and carries some risk of graft rejection. Most recipients of solid-organ transplants have multiple risk factors; the contribution of individual factors is less certain. In patients with viral hepatitis, the relative contributions of active viral infection, cirrhosis, and the treatment of these infections are unclear. Thus, as Joy indicates, in the case under consideration, the contribution of hepatitis B is most likely to be through cirrhosis and for the risk of establishment of fungal colonization in the pretransplantation period and the potential risk of viral reactivation in the context of immunosuppression after transplantation. As the shortage of donor organs persists, the use of livers that are positive for core antigen, and thus for hepatitis B DNA, is likely to increase. The full effect of the use of donor organs according to expanded criteria has yet to be ascertained.

Jay A. Fishman, M.D.
Ramon Gilberto Gonzalez, M.D.
Massachusetts General Hospital, Boston, MA 02114

1 References